Carpal Tunnel Syndrome (CTS) affects up to 4% of the US population, with higher prevalence in the working population [1, 2]. Chronic pain (CP) is one of the most common and difficult to treat complications of CTS [2-6]. Current therapies [2-11] do not directly address the fact that pain sensation is processed in the brain [5, 12-14] and most act at the neuropathy site (i.e., in the periphery), although CTS patients also have a central pain component due to their injury [5, 6, 12-15]. CTS symptomatology correlates with CP-induced changes in brain activity and/or structure [14-24]. Non-Invasive Brain Stimulation (NIBS) has been successfully applied for the treatment of CP in some disease states, where treatment induced changes in brain activity revert maladaptive plasticity associated with the perception/sensation of CP [25-28]. However, the most common NIBS methods, e.g., transcranial direct current stimulation, have shown limited, if any, efficacy in treating neuropathic pain [13, 29-33]. It has been postulated that limitations in conventional NIBS techniques? focality, penetration, and targeting control limit their therapeutic efficacy [34-38]. Electrosonic Stimulation (ESStim?) is an improved NIBS modality that overcomes the limitations of other technologies by combining independently controlled electromagnetic and ultrasonic fields to focus and boost stimulation currents via tuned electromechanical coupling in neural tissue [39]. This proposal is focused on evaluating whether our noninvasive ESStim system can effectively treat CP in CTS, both as a lone treatment and in conjunction with physical therapy (PT). In Phase I, to assess the feasibility of the proposed work, and specifically test ESStim?s ability to improve CTS pain, we will follow 20 CTS patients after giving a fixed dose of ESStim for 5 consecutive days, 20 min/day (10 SHAM ESStim, 10 ESStim). We will administer a battery of safety, pain, quantitative sensory testing (QST), motor function, and global self-assessments (e.g., QOL) evaluated over the treatment period and for at least six weeks following the last treatment session. Next in Phase II, we will assess whether ESStim induced pain reductions can be coupled with physical therapy (PT) to improve CTS treatment. We will follow 60 CTS patients (30 ESStim, 30 SHAM) after giving a fixed dose of stimulation for 10 days over two weeks, 20 min/day, but now provided in conjunction with PT. We will evaluate these patients with the battery of assessments validated in Phase I, and compare the efficacy of the tested interventions for at least eight weeks following the last treatment session. We hypothesize ESStim can be provided synergistically with PT, as both can encourage plasticity-dependent changes which could maximally improve a CTS patient?s pain free mobility. In parallel with the CTS treatments, we will build multivariate linear and generalized linear regression models to predict the CTS patient outcomes related to pain, physical function, and psychosocial assessments as a function of baseline disease characteristics. The computational work will be used to develop an optimized CTS ESStim dosing model. Overall, we hypothesize that we will be able to develop ESStim? for CTS treatment.